The major focus of this project is to understand how cells monitor and repair DNA damage. Defects in either the surveillance or repair of damaged DNA can lead to chromosomal instability and cancer. For example, inherited disorders affecting cellular responses to DNA damage, such as ataxia telangiectasia are characterized by increased susceptibility to lymphoid cancer, extreme radiation sensitivity and immunodeficiency. We are generating knockout and transgenic mouse models that have specific defects in DNA double strand break (DSB) repair through the genetic manipulation of the major players that mediate homologous recombination and non-homologous end joining DNA repair pathways. We have characterized mice that were defective in non-homologous end joining, the major pathway for repairing DSBs in mammalian cells and provided evidence for a novel mechanism for HR restoration through the inactivation of proteins functioning in an alternate DNA repair pathway called non-homologous end joining (NHEJ). Loss of the NHEJ proteins 53BP1, PTIP and RIF1 restored normal HR activity in BRCA1 deficient cells, and rendered these cells resistant to PARPi. A major aim of this research project is to understand how altering the balance between NHEJ and HR pathways can be exploited to overcome the Achilles heel of acquired resistance in breast cancer treatment. In addition to showing that one mechanism of chemoresistance is through the re-establishment of homologous recombination in the tumor, we have made the recent finding that replication fork stability can also promote survival and drive resistance to chemotherapy in BRCA1/2-mutant cancers. We are currently exploring the use of existing panels of BRCA1/2-mutant mouse and human breast carcinomas with primary or acquired chemotherapy resistance, to directly test the hypothesis that complex processes involving replication fork stability promotes survival and drives resistance to chemotherapy.